GnRH neuron

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GnRH neurons, or gonadotropin-releasing hormone expressing neurons, are the cells in the brain that control the release of reproductive hormones from the pituitary. These brain cells control reproduction by secreting GnRH into the hypophyseal portal capillary bloodstream, so are sometimes referred to as “sex neurons”. This small capillary network carries GnRH to the anterior pituitary, causing release of luteinizing hormone (LH) and follicle stimulating hormone (FSH) into the wider bloodstream. When GnRH neurons change their pattern of release from the juvenile to the adult pattern of GnRH secretion, puberty is initiated. Failure of GnRH neurons to form the proper connections, or failure to successfully stimulate the pituitary with GnRH, means that puberty is not initiated. These disruptions to the GnRH system cause reproductive disorders like hypogonadotropic hypogonadism or Kallmann Syndrome.

Contents

Fluorescence image of GnRH neurons (blue) with elements of their cellular cytoskeletons shown in red and green. GnRH Neuron.png
Fluorescence image of GnRH neurons (blue) with elements of their cellular cytoskeletons shown in red and green.

Origins of GnRH neurons

In 1989, two research groups independently discovered that GnRH neurons, which in adults are scattered throughout the hypothalamus, do not originate in this region of the brain. Instead, they migrate into the brain along olfactory axon fibers from the nose. [1] [2] Most GnRH neurons are born from stem cells in the nasal placode (embryonic nasal tissue). More recently, it was discovered that a subset of GnRH neurons can trace their origins not from the nasal placode, but from the neural crest earlier in embryogenesis. [3] This subset of cells migrates into the nasal placode, where they intermix with GnRH neurons born in this region, and migrate together into the brain.

Journey from nose to brain

On their journey from nose to brain, GnRH neurons pass through nasal tissue, the early skull, and move through several regions of the forebrain before reaching their destinations. [4] Along the way, secreted and membrane-bound molecules guide them in the right direction and help to set their movement speed. GnRH neurons that fail to enter the brain, or that migrate to the wrong region, are not functional and can even undergo programmed cell death. This failure of GnRH neurons to migrate into the brain is the main cause of Kallmann Syndrome. [5] GABA, which depolarizes embryonic GnRH neurons, slows movement but helps them to move straight along their pathway. [6] SDF activates hyperpolarizing GIRK channels, accelerating movement speeds. Other guidance cues like semaphorins [7] [8] and HGF [9] regulate movement of GnRH neurons as well.

Movement of GnRH neurons

Scientists have discovered how guidance molecules cause GnRH neurons to speed up or slow down. Normally, any calcium ions in the cell are rapidly pulled into organelles like the mitochondria or endoplasmic reticulum. Guidance molecules cause the release of these calcium ions back into the cell cytoplasm, where calcium sensing proteins re-organize the cell’s actin [10] and microtubule [11] cytoskeleton, which are the molecular filaments that give a cell its shape. This causes contractions in the cell (similar to muscle contractions) that link to adhesive proteins on the cell surface, [12] pulling the cell forward.

GnRH Physiology

The shift to high frequency electrical activity in GnRH neurons is the signal that initiates puberty. GnRH neurons receive input from classical neurotransmitters like glutamate and GABA. [13] These neurotransmitters cause electrical activity that is regulated through development to cause broad changes in calcium ion entry into the cell through voltage-sensitive ion channels. This triggers the release of GnRH into the hypophyseal portal capillary bloodstream, where the GnRH hormone activates the pituitary to release luteinizing hormone and follicle stimulating hormone. In addition to classical neurotransmitters, some guidance molecules can change the wiring of GnRH neurons to the portal capillary system, altering the strength of the signal to the pituitary gland. [14]

Regulation of GnRH neurons

GnRH neurons integrate information from the body to regulate reproduction. The strongest activator of GnRH neurons is a hormone called Kisspeptin. [15] GnRH neurons also integrate information from the body through hormones like neuropeptide Y [16] and adiponectin. [17] These hormones provide the GnRH neurons with information about the body’s status to help determine whether reproduction should be prioritized or suppressed.

Related Research Articles

<span class="mw-page-title-main">Luteinizing hormone</span> Gonadotropin secreted by the adenohypophysis

Luteinizing hormone is a hormone produced by gonadotropic cells in the anterior pituitary gland. The production of LH is regulated by gonadotropin-releasing hormone (GnRH) from the hypothalamus. In females, an acute rise of LH known as an LH surge, triggers ovulation and development of the corpus luteum. In males, where LH had also been called interstitial cell–stimulating hormone (ICSH), it stimulates Leydig cell production of testosterone. It acts synergistically with follicle-stimulating hormone (FSH).

<span class="mw-page-title-main">Gonadotropin-releasing hormone</span> Mammalian protein found in Homo sapiens

Gonadotropin-releasing hormone (GnRH) is a releasing hormone responsible for the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. GnRH is a tropic peptide hormone synthesized and released from GnRH neurons within the hypothalamus. The peptide belongs to gonadotropin-releasing hormone family. It constitutes the initial step in the hypothalamic–pituitary–gonadal axis.

<span class="mw-page-title-main">Arcuate nucleus</span>

The arcuate nucleus of the hypothalamus is an aggregation of neurons in the mediobasal hypothalamus, adjacent to the third ventricle and the median eminence. The arcuate nucleus includes several important and diverse populations of neurons that help mediate different neuroendocrine and physiological functions, including neuroendocrine neurons, centrally projecting neurons, and astrocytes. The populations of neurons found in the arcuate nucleus are based on the hormones they secrete or interact with and are responsible for hypothalamic function, such as regulating hormones released from the pituitary gland or secreting their own hormones. Neurons in this region are also responsible for integrating information and providing inputs to other nuclei in the hypothalamus or inputs to areas outside this region of the brain. These neurons, generated from the ventral part of the periventricular epithelium during embryonic development, locate dorsally in the hypothalamus, becoming part of the ventromedial hypothalamic region. The function of the arcuate nucleus relies on its diversity of neurons, but its central role is involved in homeostasis. The arcuate nucleus provides many physiological roles involved in feeding, metabolism, fertility, and cardiovascular regulation.

Kallmann syndrome (KS) is a genetic disorder that prevents a person from starting or fully completing puberty. Kallmann syndrome is a form of a group of conditions termed hypogonadotropic hypogonadism. To distinguish it from other forms of hypogonadotropic hypogonadism, Kallmann syndrome has the additional symptom of a total lack of sense of smell (anosmia) or a reduced sense of smell. If left untreated, people will have poorly defined secondary sexual characteristics, show signs of hypogonadism, almost invariably are infertile and are at increased risk of developing osteoporosis. A range of other physical symptoms affecting the face, hands and skeletal system can also occur.

Neuroendocrine cells are cells that receive neuronal input and, as a consequence of this input, release messenger molecules (hormones) into the blood. In this way they bring about an integration between the nervous system and the endocrine system, a process known as neuroendocrine integration. An example of a neuroendocrine cell is a cell of the adrenal medulla, which releases adrenaline to the blood. The adrenal medullary cells are controlled by the sympathetic division of the autonomic nervous system. These cells are modified postganglionic neurons. Autonomic nerve fibers lead directly to them from the central nervous system. The adrenal medullary hormones are kept in vesicles much in the same way neurotransmitters are kept in neuronal vesicles. Hormonal effects can last up to ten times longer than those of neurotransmitters. Sympathetic nerve fiber impulses stimulate the release of adrenal medullary hormones. In this way the sympathetic division of the autonomic nervous system and the medullary secretions function together.

Neuroendocrinology is the branch of biology which studies the interaction between the nervous system and the endocrine system; i.e. how the brain regulates the hormonal activity in the body. The nervous and endocrine systems often act together in a process called neuroendocrine integration, to regulate the physiological processes of the human body. Neuroendocrinology arose from the recognition that the brain, especially the hypothalamus, controls secretion of pituitary gland hormones, and has subsequently expanded to investigate numerous interconnections of the endocrine and nervous systems.

<span class="mw-page-title-main">Hypothalamic–pituitary–gonadal axis</span> Concept of regarding the hypothalamus, pituitary gland and gonadal glands as a single entity

The hypothalamic–pituitary–gonadal axis refers to the hypothalamus, pituitary gland, and gonadal glands as if these individual endocrine glands were a single entity. Because these glands often act in concert, physiologists and endocrinologists find it convenient and descriptive to speak of them as a single system.

Isolated hypogonadotropic hypogonadism (IHH), also called idiopathic or congenital hypogonadotropic hypogonadism (CHH), as well as isolated or congenital gonadotropin-releasing hormone deficiency (IGD), is a condition which results in a small subset of cases of hypogonadotropic hypogonadism (HH) due to deficiency in or insensitivity to gonadotropin-releasing hormone (GnRH) where the function and anatomy of the anterior pituitary is otherwise normal and secondary causes of HH are not present.

<span class="mw-page-title-main">Gonadotropin-releasing hormone agonist</span> Drug class affecting sex hormones

A gonadotropin-releasing hormone agonist is a type of medication which affects gonadotropins and sex hormones. They are used for a variety of indications including in fertility medicine and to lower sex hormone levels in the treatment of hormone-sensitive cancers such as prostate cancer and breast cancer, certain gynecological disorders like heavy periods and endometriosis, high testosterone levels in women, early puberty in children, as a part of transgender hormone therapy, and to delay puberty in transgender youth among other uses. It is also used in the suppression of spontaneous ovulation as part of controlled ovarian hyperstimulation, an essential component in IVF. GnRH agonists are given by injections into fat, as implants placed into fat, and as nasal sprays.

The gonadotropin-releasing hormone receptor (GnRHR), also known as the luteinizing hormone releasing hormone receptor (LHRHR), is a member of the seven-transmembrane, G-protein coupled receptor (GPCR) family. It is the receptor of gonadotropin-releasing hormone (GnRH). The GnRHR is expressed on the surface of pituitary gonadotrope cells as well as lymphocytes, breast, ovary, and prostate.

<span class="mw-page-title-main">Kisspeptin</span> Mammalian protein

Kisspeptins are proteins encoded by the KISS1 gene in humans. Kisspeptins are ligands of the G-protein coupled receptor, GPR54. Kiss1 was originally identified as a human metastasis suppressor gene that has the ability to suppress melanoma and breast cancer metastasis. Kisspeptin-GPR54 signaling has an important role in initiating secretion of gonadotropin-releasing hormone (GnRH) at puberty, the extent of which is an area of ongoing research. Gonadotropin-releasing hormone is released from the hypothalamus to act on the anterior pituitary triggering the release of luteinizing hormone (LH), and follicle stimulating hormone (FSH). These gonadotropic hormones lead to sexual maturation and gametogenesis. Disrupting GPR54 signaling can cause hypogonadotrophic hypogonadism in rodents and humans. The Kiss1 gene is located on chromosome 1. It is transcribed in the brain, adrenal gland, and pancreas.

<span class="mw-page-title-main">Neurokinin B</span> Chemical compound

Neurokinin B (NKB) belongs in the family of tachykinin peptides. Neurokinin B is implicated in a variety of human functions and pathways such as the secretion of gonadotropin-releasing hormone. Additionally, NKB is associated with pregnancy in females and maturation in young adults. Reproductive function is highly dependent on levels of both neurokinin B and also the G-protein coupled receptor ligand kisspeptin. The first NKB studies done attempted to resolve why high levels of the peptide may be implicated in pre-eclampsia during pregnancy. NKB, kisspeptin, and dynorphin together are found in the arcuate nucleus (ARC) known as the KNDy subpopulation. This subpopulation is targeted by many steroid hormones and works to form a network that feeds back to GnRH pulse generator.

<span class="mw-page-title-main">GNRHR</span> Protein-coding gene in the species Homo sapiens

Gonadotropin-releasing hormone receptor is a protein that in humans is encoded by the GNRHR gene.

The development of the nervous system in humans, or neural development or neurodevelopment involves the studies of embryology, developmental biology, and neuroscience to describe the cellular and molecular mechanisms by which the complex nervous system forms in humans, develops during prenatal development, and continues to develop postnatally.

<span class="mw-page-title-main">KiSS1-derived peptide receptor</span> Mammalian protein found in Homo sapiens

The KiSS1-derived peptide receptor is a G protein-coupled receptor which binds the peptide hormone kisspeptin (metastin). Kisspeptin is encoded by the metastasis suppressor gene KISS1, which is expressed in a variety of endocrine and gonadal tissues. Activation of the kisspeptin receptor is linked to the phospholipase C and inositol trisphosphate second messenger cascades inside the cell.

Gonadotropin-releasing hormone (GnRH) insensitivity also known as Isolated gonadotropin-releasing hormone (GnRH)deficiency (IGD) is a rare autosomal recessive genetic and endocrine syndrome which is characterized by inactivating mutations of the gonadotropin-releasing hormone receptor (GnRHR) and thus an insensitivity of the receptor to gonadotropin-releasing hormone (GnRH), resulting in a partial or complete loss of the ability of the gonads to synthesize the sex hormones. The condition manifests itself as isolated hypogonadotropic hypogonadism (IHH), presenting with symptoms such as delayed, reduced, or absent puberty, low or complete lack of libido, and infertility, and is the predominant cause of IHH when it does not present alongside anosmia.

Hypogonadotropic hypogonadism (HH), is due to problems with either the hypothalamus or pituitary gland affecting the hypothalamic-pituitary-gonadal axis. Hypothalamic disorders result from a deficiency in the release of gonadotropic releasing hormone (GnRH), while pituitary gland disorders are due to a deficiency in the release of gonadotropins from the anterior pituitary. GnRH is the central regulator in reproductive function and sexual development via the HPG axis. GnRH is released by GnRH neurons, which are hypothalamic neuroendocrine cells, into the hypophyseal portal system acting on gonadotrophs in the anterior pituitary. The release of gonadotropins, LH and FSH, act on the gonads for the development and maintenance of proper adult reproductive physiology. LH acts on Leydig cells in the male testes and theca cells in the female. FSH acts on Sertoli cells in the male and follicular cells in the female. Combined this causes the secretion of gonadal sex steroids and the initiation of folliculogenesis and spermatogenesis. The production of sex steroids forms a negative feedback loop acting on both the anterior pituitary and hypothalamus causing a pulsatile secretion of GnRH. GnRH neurons lack sex steroid receptors and mediators such as kisspeptin stimulate GnRH neurons for pulsatile secretion of GnRH.

Pulsatile secretion is a biochemical phenomenon observed in a wide variety of cell and tissue types, in which chemical products are secreted in a regular temporal pattern. The most common cellular products observed to be released in this manner are intercellular signaling molecules such as hormones or neurotransmitters. Examples of hormones that are secreted pulsatilely include insulin, thyrotropin, TRH, gonadotropin-releasing hormone (GnRH) and growth hormone (GH). In the nervous system, pulsatility is observed in oscillatory activity from central pattern generators. In the heart, pacemakers are able to work and secrete in a pulsatile manner. A pulsatile secretion pattern is critical to the function of many hormones in order to maintain the delicate homeostatic balance necessary for essential life processes, such as development and reproduction. Variations of the concentration in a certain frequency can be critical to hormone function, as evidenced by the case of GnRH agonists, which cause functional inhibition of the receptor for GnRH due to profound downregulation in response to constant (tonic) stimulation. Pulsatility may function to sensitize target tissues to the hormone of interest and upregulate receptors, leading to improved responses. This heightened response may have served to improve the animal's fitness in its environment and promote its evolutionary retention.

Gonadotropin surge-attenuating factor (GnSAF) is a nonsteroidal ovarian hormone produced by the granulosa cells of small antral ovarian follicles in females. GnSAF is involved in regulating the secretion of luteinizing hormone (LH) from the anterior pituitary and the ovarian cycle. During the early to mid-follicular phase of the ovarian cycle, GnSAF acts on the anterior pituitary to attenuate LH release, limiting the secretion of LH to only basal levels. At the transition between follicular and luteal phase, GnSAF bioactivity declines sufficiently to permit LH secretion above basal levels, resulting in the mid-cycle LH surge that initiates ovulation. In normally ovulating women, the LH surge only occurs when the oocyte is mature and ready for extrusion. GnSAF bioactivity is responsible for the synchronised, biphasic nature of LH secretion.

Gonadotropin-inhibitory hormone (GnIH) is a RFamide-related peptide coded by the NPVF gene in mammals.

References

  1. ↑ Schwanzel-Fukuda, M; Pfaff, DW (1989). "Origin of luteinizing hormone-releasing hormone neurons". Nature. 338 (6211): 161–4. Bibcode:1989Natur.338..161S. doi:10.1038/338161a0. PMID   2645530. S2CID   4310861.
  2. ↑ Wray, S; Grant, P; Gainer, H (1989). "Evidence that cells expressing luteinizing hormone-releasing hormone mRNA in the mouse are derived from progenitor cells in the olfactory placode". Proceedings of the National Academy of Sciences. 86 (20): 8132–6. Bibcode:1989PNAS...86.8132W. doi: 10.1073/pnas.86.20.8132 . PMC   298229 . PMID   2682637.
  3. ↑ Forni, PE; Taylor-Burds, C; Melvin, VS; Williams, T; Wray, S (2011). "Neural crest and ectodermal cells intermix in the nasal placode to give rise to GnRH-1 neurons, sensory neurons, and olfactory ensheathing cells". Journal of Neuroscience. 31 (18): 6915–27. doi:10.1523/JNEUROSCI.6087-10.2011. PMC   3101109 . PMID   21543621.
  4. ↑ Wray, S (2010). "From nose to brain: development of gonadotrophin-releasing hormone-1 neurones". Journal of Neuroendocrinology. 22 (7): 743–53. doi:10.1111/j.1365-2826.2010.02034.x. PMC   2919238 . PMID   20646175.
  5. ↑ Valdes-Socin, H (2014). "Reproduction, smell, and neurodevelopmental disorders: genetic defects in different hypogonadotropic hypogonadal syndromes" (PDF). Frontiers in Endocrinology. 5: 109. doi: 10.3389/fendo.2014.00109 . PMC   4088923 . PMID   25071724.
  6. ↑ Casoni, F; Hutchins, BI; Donohue, D; Fornaro, M; Condie, BG; Wray, S (2012). "SDF and GABA interact to regulate axophilic migration of GnRH neurons". Journal of Cell Science. 125 (21): 5015–25. doi:10.1242/jcs.101675. PMC   3533389 . PMID   22976302.
  7. ↑ Giacobini, P (2008). "Semaphorin 4D regulates gonadotropin hormone-releasing hormone-1 neuronal migration through PlexinB1-Met complex". Journal of Cell Biology. 183 (3): 555–66. doi:10.1083/jcb.200806160. PMC   2575794 . PMID   18981235.
  8. ↑ Messina, Andrea; Ferraris, Nicoletta; Wray, Susan; Cagnoni, Gabriella; Donohue, Duncan E.; Casoni, Filippo; Kramer, Phillip R.; Derijck, Alwin A.; Adolfs, Youri (2011-12-15). "Dysregulation of Semaphorin7A/β1-integrin signaling leads to defective GnRH-1 cell migration, abnormal gonadal development and altered fertility". Human Molecular Genetics. 20 (24): 4759–4774. doi:10.1093/hmg/ddr403. ISSN   0964-6906. PMC   3221532 . PMID   21903667.
  9. ↑ Giacobini, P (2007). "Hepatocyte growth factor acts as a motogen and guidance signal for gonadotropin hormone-releasing hormone-1 neuronal migration" (PDF). Journal of Neuroscience. 27 (2): 431–45. doi:10.1523/JNEUROSCI.4979-06.2007. PMC   6672060 . PMID   17215404.
  10. ↑ Hutchins, BI; Klenke, U; Wray, S (2013). "Calcium release-dependent actin flow in the leading process mediates axophilic migration". Journal of Neuroscience. 33 (28): 11361–71. doi:10.1523/JNEUROSCI.3758-12.2013. PMC   3724331 . PMID   23843509.
  11. ↑ Hutchins, BI; Wray, S (2014). "Capture of microtubule plus-ends at the actin cortex promotes axophilic neuronal migration by enhancing microtubule tension in the leading process". Frontiers in Cellular Neuroscience. 8: 400. doi: 10.3389/fncel.2014.00400 . PMC   4245908 . PMID   25505874.
  12. ↑ Parkash, J (2012). "Suppression of β1-integrin in gonadotropin-releasing hormone cells disrupts migration and axonal extension resulting in severe reproductive alterations". Journal of Neuroscience. 32 (47): 16992–7002. doi:10.1523/JNEUROSCI.3057-12.2012. PMC   5238668 . PMID   23175850.
  13. ↑ Constantin, S; Klenke, U; Wray, S (2010). "The calcium oscillator of GnRH-1 neurons is developmentally regulated". Endocrinology. 151 (8): 3863–73. doi:10.1210/en.2010-0118. PMC   2940530 . PMID   20555030.
  14. ↑ Giacobini, P (2014). "Brain endothelial cells control fertility through ovarian-steroid-dependent release of semaphorin 3A". PLOS Biology. 12 (3): e1001808. doi: 10.1371/journal.pbio.1001808 . PMC   3949669 . PMID   24618750.
  15. ↑ de Roux, N; Genin, E; Carel, JC; Matsuda, F; Chaussain, JL; Milgrom, E (2003). "Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54". Proceedings of the National Academy of Sciences. 100 (19): 10972–6. Bibcode:2003PNAS..10010972D. doi: 10.1073/pnas.1834399100 . PMC   196911 . PMID   12944565.
  16. ↑ Klenke, U; Constantin, S; Wray, S (2010). "Neuropeptide Y directly inhibits neuronal activity in a subpopulation of gonadotropin-releasing hormone-1 neurons via Y1 receptors". Endocrinology. 151 (6): 2736–46. doi:10.1210/en.2009-1198. PMC   2875836 . PMID   20351316.
  17. ↑ Klenke, U; Taylor-Burds, C; Wray, S (2014). "Metabolic influences on reproduction: adiponectin attenuates GnRH neuronal activity in female mice". Endocrinology. 155 (5): 1851–63. doi:10.1210/en.2013-1677. PMC   3990841 . PMID   24564393.
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